Dissecting DNA repair in adult high grade gliomas for patient stratification in the post-genomic era
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Christina Perry1, Devika Agarwal2, Tarek M.A. Abdel-Fatah3, Anbarasu Lourdusamy4, Richard Grundy4, Dorothee T. Auer 5, David Walker4, Ravi Lakhani6, Ian S. Scott 7, Stephen Chan3, Graham Ball2 and Srinivasan Madhusudan1,3
1 Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, UK
2 School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, UK
3 Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
4 Children’s Brain Tumour Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen’s Medical Centre, Nottingham University Hospitals, Nottingham, UK
5 Department of Academic Radiology, University of Nottingham, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, UK
6 University of Leicester Medical School, Maurice Shock Building, University Road, Leicester, UK
7 Department of Neuropathology, Nottingham University Hospitals, Queen’s Medical Centre, Nottingham, UK
Srinivasan Madhusudan, email:
Keywords: DNA repair; high grade glioma; glioblastoma; prognostic factor; biomarker
Received: June 10, 2014 Accepted: July 8, 2014 Published: July 9, 2014
Deregulation of multiple DNA repair pathways may contribute to aggressive biology and therapy resistance in gliomas. We evaluated transcript levels of 157 genes involved in DNA repair in an adult glioblastoma Test set (n=191) and validated in ‘The Cancer Genome Atlas’ (TCGA) cohort (n=508). A DNA repair prognostic index model was generated. Artificial neural network analysis (ANN) was conducted to investigate global gene interactions. Protein expression by immunohistochemistry was conducted in 61 tumours. A fourteen DNA repair gene expression panel was associated with poor survival in Test and TCGA cohorts. A Cox multivariate model revealed APE1, NBN, PMS2, MGMT and PTEN as independently associated with poor prognosis. A DNA repair prognostic index incorporating APE1, NBN, PMS2, MGMT and PTEN stratified patients in to three prognostic sub-groups with worsening survival. APE1, NBN, PMS2, MGMT and PTEN also have predictive significance in patients who received chemotherapy and/or radiotherapy. ANN analysis of APE1, NBN, PMS2, MGMT and PTEN revealed interactions with genes involved in transcription, hypoxia and metabolic regulation. At the protein level, low APE1 and low PTEN remain associated with poor prognosis. In conclusion, multiple DNA repair pathways operate to influence biology and clinical outcomes in adult high grade gliomas.
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